Whitten was originally a very conservative segregationist, as were many of his colleagues from Mississippi and the rest of the South. He signed the Southern Manifesto condemning the U.S. Supreme Court decision Brown vs. Board of Education, which desegregated public schools. Along with virtually the entire Mississippi congressional delegation, he voted against the Civil Rights Acts of 1957, 1960, 1964, 1965 and 1968. Whitten later apologized for these votes, calling them a "mistake" caused by severe misjudgment. He voted for the Civil Rights Act of 1991. As a champion for large farming operations, he fought against the FDA's early 1970's recommendation of restricting the use of antibiotics as the FDA was concerned about the developing of drug resistant bacteria as a result. Whitten threatened to pull budgets if the FDA continue with this direction.[2]

Later in his career he shifted to the left, supporting a number of liberal issues and frequently clashed with the Reagan administration on policy matters. He voted against Reagan's economic plans, tax cuts, increased defense spending, balanced budget initiative, tort reform, welfare reform, abortion restrictions, missile defense system, and the Persian Gulf War. Although Whitten represented a district that grew increasingly suburban and Republican from the 1970s onward, his opposition to Reagan's program did not affect him at the ballot box. Indeed, his seniority and popularity resulted in him facing only "sacrificial lamb" opponents on the occasions he faced any opposition at all. Nonetheless, it was taken for granted that he would be succeeded by a Republican when he retired.

Declining to run for reelection to a historic 28th term in 1994, Whitten retired from the House as America's longest serving Congressman (53 years and two months). He retired to his home in Oxford, Mississippi and died there on September 9, 1995, aged 85, eight months after he was indeed succeeded by a Republican, Roger Wicker.